Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

Laurent Meijer, Deborah J Nelson, Vladimir Riazanski, Aida G Gabdoulkhakova, Geneviève Hery-Arnaud, Rozenn Le Berre, Nadège Loaëc, Nassima Oumata, Hervé Galons, Emmanuel Nowak, Laetitia Gueganton, Guillaume Dorothée, Michaela Prochazkova, Bradford Hall, Ashok B Kulkarni, Robert D Gray, Adriano G Rossi, Véronique Witko-Sarsat, Caroline Norez, Frédéric BecqDenis Ravel, Dominique Mottier, Gilles Rault

Research output: Contribution to journalLiterature reviewpeer-review

Abstract / Description of output

(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

Original languageEnglish
JournalJournal of Innate Immunity
DOIs
Publication statusPublished - 18 Mar 2016

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